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Smooth muscle cell of the canine prostate in spontaneous benign hyperplasia, steroid induced hyperplasia and estrogen or tamoxifen treated dogs.

Human benign prostatic hyperplasia is a predominantly stromal hyperplasia with accumulation of connective tissue. The main ultrastructural finding, which may be causal, is an activation of the smooth muscle cells, as seen by an increase of the volume density of the organelles within these cells. The dog is widely used as an animal model for human prostatic hyperplasia in spite of several differences. In this work the smooth muscle cells of the spontaneous and steroid-induced (by treating castrates with dihydrotestosterone and estradiol) prostatic hyperplasia of dogs were analysed by electron microscopical morphometry, and compared to estrogen or tamoxifen (antiestrogen) treated dogs as well as to untreated or castrated control dogs. The results clearly show that the prostatic smooth muscle cells of the dog can be activated by estrogen as well as tamoxifen, which proves the estrogenic side activity of the latter. In marked contrast to that, neither in the spontaneous nor in the steroid-induced prostatic hyperplasia could an activation of the smooth muscle cells be found. This is a most important difference from human benign prostatic hyperplasia, which limits the use of this animal model, and it might even be the explanation of the different reaction of human and canine prostatic hyperplasia to therapeutic hormonal manipulations.

Animals↗

Estrogenic/antiestrogenic and scavenging properties of (E)- and (Z)-resveratrol.

Resveratrol, natural compound found in grapes and wine, has been reported to have a variety of health benefit properties. Based on the structural similarity to the synthetic estrogen diethylstilbestrol, we investigated estrogenic/antiestrogenic effects on human breast cancer cell lines, MCF-7 and MVLN, and scavenging properties using DPPH of both (E)- and (Z)-isomers. Both isomers increased the in vitro growth of MCF-7 cell lines at medium concentrations (10 and 25 microM) whereas the low concentrations (0.1 and 1 microM) had no effect and the high concentration (50 microM) decreased the cell growth and was cytotoxic. The 25 microM (E)-isomer alone was able to reduced the proliferation induced by the estradiol. Low concentrations of (E)- and (Z)-resveratrol (0.1 and 1 microM) and medium concentration 10 microM (Z)-resveratrol did not interfere with the estrogen receptor. In contrast, medium concentrations of (E)-resveratrol (10 and 25 microM) and (Z)-resveratrol (25 microM) functioned as superagonists of estradiol. Whatever the model used, MCF-7 or MVLN cell lines, (Z)-resveratrol was less effective than (E)-resveratrol. Extinction of DPPH and Fe(III) reduction experiments showed that both isomers of resveratrol could act as free radicals scavengers or pro-oxidant compounds. The properties of low concentrations of resveratrol raise the possibility that structure-function studies could lead to the development of more selective estrogen receptor agonists and antagonists, which could be useful as a therapeutic agent.

Cell Division↗

Effect of gender and sex hormones on immune responses following shock.

Several clinical and experimental studies show a gender dimorphism of the immune and organ responsiveness in the susceptibility to and morbidity from shock, trauma, and sepsis. In this respect, cell-mediated immune responses are depressed in males after trauma-hemorrhage, whereas they are unchanged or enhanced in females. Sex hormones contribute to this gender-specific immune response after adverse circulatory conditions. Specifically, studies indicate that androgens are responsible for the immunodepression after trauma-hemorrhage in males. In contrast, female sex steroids seem to exhibit immunoprotective properties after trauma and severe blood loss, because administration of estrogen prevents the androgen-induced immunodepression in castrated male mice. Nonetheless, the precise underlying mechanisms for these immunomodulatory effects of sex steroids after shock remain unknown. Although testosterone depletion, testosterone receptor antagonism, or estrogen treatment has been shown to prevent the depression of immune functions after trauma-hemorrhage, it remains to be established whether differences in the testosterone-estradiol ratio are responsible for the immune dysfunction. Furthermore, sex hormone receptors have been identified on various immune cells, suggesting direct effects. Thus, the immunomodulatory properties of sex hormones after trauma-hemorrhage might represent novel therapeutic strategies for the treatment of immunodepression in trauma patients.

Androgen Antagonists↗

3H-estradiol and 3H-R5020 binding in cytosols of normal and neoplastic human ovarian tissue.

High-affinity cytoplasmic estrogen and progesterone receptors in normal and abnormal ovarian tissues were studied. Estradiol receptor was detectable in 65% and progesterone receptor in 36% of the malignant tumors; 39% of all malignant ovarian tissues were estradiol- as well as progesterone-receptor-positive. Tumors were said to be receptor-positive when the receptors bound greater than 5 fM steroid/mg cytosol protein. No correlations were found between receptor status and histopathological diagnosis. In normal ovarian tissues collected at various phases of the menstrual cycle no changes in [3H]-estradiol and [3H]-R5020 binding could be detected. Analysis of the receptor concentration for both steroid hormones with regard to the menopausal status demonstrated highest levels in postmenopausal women. No significant difference could be found when two groups of patients with advanced ovarian carcinoma associated with the cytosol estrogen receptor status were compared in terms of two different therapeutic schemes (cytosolic chemotherapy with and without tamoxifen).

Cytosol↗

The mechanism of prostaglandin action on the pregnant human uterus.

The concentrations of 15 methyl PGF2 alpha, progesterone and estradiol in the peripheral plasma were assayed sequentially and the resting and active pressures of the uterus were quantitated in 10 first trimester pregnant patients, treated with a vaginal suppository containing 3 mg U-36,384. The purpose of the study was to determine the sequence of the prostaglandin induced changes in regulatory profile and uterine function and thus expose further the mechanism of prostaglandin action. The temporal relationships of the changes revealed that the primary action of exogenous prostaglandin is the disruption of the normal endocrine function of the conceptus and that the delayed oxytocic effect of this compound is secondary, a consequence of the primary action. Apparently prostaglandins are only effective as postconceptional agents if they convert the refractory normal pregnant uterus into a reactive organ. The academic and therapeutic significance of this finding is discussed.

Abortifacient Agents↗

Effects of switching to wen-jing-tang (unkei-to) from preceding herbal preparations selected by eight-principle pattern identification on endocrinological status and ovulatory induction in women with polycystic ovary syndrome.

The objective of this study was to investigate the effects of switching therapy to wen-jing-tang (unkei-to) from previous selected herbal preparations on endocrine levels and induction of ovulation in women with polycystic ovary syndrome (PCOS). Sixty-four anovulatory women diagnosed with PCOS were enrolled in the study. After Kampo diagnosis, subjects received matched Kampo preparations (43 cases: dang-gui-shao-yao-san, 21 cases: gui-zhi-fu-ling-wan) selected by the matching theory of eight-principle pattern identification and Kampo diagnosis based on concepts of the qi, blood, and fluids as the physiologic activity. Fifty-four women who failed to ovulate after an 8-week treatment were randomly allocated to continuation of treatment with the preceding Kampo prescription (continuation group, n = 27) or treatment with wen-jing-tang (switching group, n = 27). Plasma FSH, LH and estradiol levels were measured and ovulation rates were determined at the beginning and after an 8-week treatment with the preceding Kampo prescription, as well as after the subsequent 8-week treatment with the same preparation or wen-jing-tang. No decrease in mean plasma LH level was observed in the 54 women who failed to ovulate among the 64 treated with a Kampo preparation. After the 8-week treatment with wen-jing-tang, plasma LH levels were decreased by 58.2% (p < 0.0001) and 49.4% (p = 0.0005) in the groups switched from dang-gui-shao-yao-san and gui-zhi-fu-ling-wan, respectively. In the group switched from dang-gui-shao-yao-san, a tendency towards increase in plasma estradiol level was observed (1.51-fold, p = 0.055), which was significant compared with that in the group switched from gui-zhi-fu-ling-wan (p = 0.032). The ovulation rate with switching of treatment to wen-jing-tang was significantly higher (59.3%) than that with continued use of the same preparation (7.4%, p = 0.0036). This study confirmed that wen-jing-tang was effective in improving endocrine condition in the treatment of disturbances of ovulation in patients with PCOS without taking eight-principle pattern identification into consideration. This finding indicates that wen-jing-tang is appropriate for use in treating PCOS in women with various constitutions (as determined by the matching theory of eight-principle pattern identification) in clinical practice and may prove to be a potent therapeutic agent with a wide therapeutic spectrum.

Adolescent↗

[Acceptability, tolerance and quality of life impact of cyproterone acetate treatment in female hirsutism. Comparison of 2 protocols in combination with oral or transdermal estradiol].

67 women (aged 16-40) with hirsutism and/or other signs of hyperandrogenism (acne, androgenic alopecia, cycle disturbances) have been treated for one year with cyproterone acetate + estradiol. Patients have been randomly assigned to therapy with cyproterone acetate and estradiol valerate per or cyproterone acetate and transdermal estradiol. Acceptance, tolerance and effects on quality of life of this treatment have been assessed using a self questionnaire completed with questions for assessment for compliance. Among patients who have had a full course of treatment, 54 have fulfilled the end-of-study quality of life questionnaire. The queries allow calculation of a relational well-being score and of an emotional well-being score. The answers to the initial questionnaire show in a high percentage of patients emotional trouble (depressive state, anxiety, irritability) and disturbances in relational life. The hirsutism score has been found to be significantly correlated with anxious trouble but not with the global quality of life score. The treatment has resulted in a significant improvement in acceptance of being exposed to view (p < 0.01), self-assurance (p < 0.01) as well as emotional well-being score (p < 0.05), without any significant difference between the 2 therapeutics groups. Measurement of treatment acceptance with a visual analogic scale has been found globally very satisfactory by patients from the 2 groups. Compliance of treatment with transdermal estradiol turned out to be lesser in younger patients but is better in patients in whom emotional balance has been improved by therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗

Neuroimmunoprotective effects of estrogen and derivatives in experimental autoimmune encephalomyelitis: therapeutic implications for multiple sclerosis.

The extensive literature and the work from our laboratory illustrate the large number of complex processes affected by estrogen that might contribute to the striking ability of 17beta-estradiol (E2) and its derivatives to inhibit clinical and histological signs of experimental autoimmune encephalomyelitis (EAE) in mice. These effects require sustained exposure to relatively low doses of exogenous hormone and offer better protection when initiated prior to induction of EAE. However, oral ethinyl estradiol (EE) and fluasterone, which lacks estrogenic side effects, could partially reverse clinical EAE when given after the onset of disease. The three main areas discussed in this review include E2-mediated inhibition of encephalitogenic T cells, inhibition of cell migration into central nervous system tissue, and neuroprotective effects that promote axon and myelin survival. E2 effects on EAE were mediated through Esr1 (alpha receptor for E2) but not Esr2 (beta receptor for E2), as were its antiinflammatory and neuroprotective effects. A novel finding is that E2 up-regulated the expression of Foxp3 and CTLA-4 that contribute to the activity of CD4+CD25+ Treg cells. The protective effects of E2 in EAE suggest its use as therapy for MS, although the risk of cardiovascular disease may complicate treatment in postmenopausal women. This risk could be minimized by using subpregnancy levels of exogenous E2 that produced synergistic effects when used in combination another immunoregulatory therapy. Alternatively, one might envision using EE or fluasterone metabolites alone or in combination therapies in both male and female MS patients.

Animals↗

Exploration of the therapeutic potential of the antiestrogen RU 58668 in breast cancer treatment.

The recently described pure antiestrogen RU 58668 displayed potent antiproliferative activities in vitro on several ER+ human mammary cell lines, stimulated either by estradiol or by endogenous or exogenous growth factors. Moreover, when administered to nude mice it proved to be the only antiestrogen to induce regression (at least 10 weeks) of estradiol-stimulated MCF-7 tumors, whereas tamoxifen only stabilized the tumor volume for 4 to 8 weeks. So the first purpose of this work was to study the effect of RU 58668 for 6 months and to evaluate its activity on tumors which escaped from the tamoxifen treatment. On the other hand, we looked for its effect on models more related to frequently described clinical observations, such as the overexpression of an oncogene or the implication of autocrine or paracrine growth factors. Long-term studies of RU 58668 on the estradiol-stimulated MCF-7 model showed that this compound induced a shrinking of tumor volumes for at least 25 weeks (3 to 6 times longer than the stabilization induced by tamoxifen) and was able to reduce the volume of tumors which escaped from, or even were stimulated by, tamoxifen. On models of spontaneously growing tumors, where the overexpression of an oncogene or the production of growth factors was involved, RU 58668 induced the same tumor shrinking that was previously observed on estradiol- or tamoxifen-stimulated models. Finally, when MCF-7 cells were injected in the uteri, a spontaneous tumor take was observed (in about 80-90% of the animals), leading to a more than twofold increase in uterus weight. This growth is largely stimulated by estradiol and tamoxifen. On this model, histological examination showed that only 30% of the animals receiving RU 58668 displayed tumoral microfoci. These studies suggest that RU 58668 may be used for the treatment of ER+ patients which are primarily resistant to or which escaped from tamoxifen treatment. Its preventive activity on tumor take also suggests its use as an adjuvant to prevent the development of metastases.

Animals↗

Antiinflammatory effects of estrogen on microglial activation.

In the present study the effects of 17beta-estradiol on microglial activation are described. Estrogen replacement therapy has been associated with decreased severity of age-related neurodegenerative diseases such as Alzheimer's disease, and estrogens have potent immunosuppressive properties outside of the brain. To determine the role that microglial cells might play in estrogen-mediated neuroprotection, primary rat microglia and N9 microglial cell lines were treated with increasing doses of 17beta-estradiol before or during immunostimulation by lipopolysaccharide, phorbol ester, or interferon-gamma. Pretreatment with 17beta-estradiol, but not 17alpha-estradiol or progesterone, dose dependently attenuated microglial superoxide release and phagocytic activity. Additionally, 17beta-estradiol attenuated increases in inducible nitric oxide synthase protein expression, but did not alter nuclear factor-KB activation. The antiinflammatory effects of 17beta-estradiol were blocked by the antiestrogen ICI 182,780. Additionally, 17beta-estradiol induced rapid phosphorylation of the p42/p44 mitogen-activated protein kinase (MAP kinase), and the MAP kinase inhibitor PD 98059 blocked the antiinflammatory effects of 17beta-estradiol. Overall, these results suggest that estrogen receptor-dependent activation of MAP kinase is involved in estrogen-mediated antiinflammatory pathways in microglial cells. These results describe a novel mechanism by which estrogen may attenuate the progression of neurodegenerative disease and suggest new pathways for therapeutic intervention in clinical settings.

Animals↗

Estrone sulfatase activity and effect of antiestrogens on transformation of estrone sulfate in hormone-dependent vs. independent human breast cancer cell lines.

The effect of the anti-estrogens ICI 164,384 and tamoxifen on the estradiol (E2) concentration after incubation of estrone sulfate (E1-S) with different hormone-dependent (MCF-7 and T-47D) and hormone-independent (MDA-MD-231 and MDA-MB-436) mammary cancer cells, as well as the estrone sulfatase activity in these various cell lines, are presented. The anti-estrogen ICI 164,384 decreased very significantly the concentration of E2 after incubation of E1-S with MCF-7 (control, mean +/- SE: 100 +/- 24 pg/mg DNA; + ICI 164,384 [10(-6)M]: 7 +/- 2 pg/mg DNA). This effect was much more intense than with tamoxifen. A similar effect was observed with T-47D cells. However, no significant effect was observed in the hormone-independent cells. In the intact cell, estrone sulfatase activity was very intense in the hormone-dependent cells, but very small in the hormone-independent cells. However, this activity became very strong after homogenization in the hormone-independent cells. The data suggest that estrone sulfate can play an important role on the bioavailability of E2 in hormone-dependent breast cancer, and that understanding the control of estrone sulfatase activity can open new knowledge of the estrogen responses and new possibilities of therapeutic application in breast cancer.

Breast Neoplasms↗

Inhibitory and stimulatory actions of danazol in rat ovarian and uterine tissues.

We examined whether danazol has a direct action on ovarian steroid secretion and/or uterine prostaglandin (PG) F2 alpha catabolic activity in immature rats in which the first ovulation was induced and in adult ovariectomized rats. The preovulatory surge of estradiol and progesterone was markedly suppressed together with that of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by danazol administration under conditions that blocked the first ovulation. Uterine weight and PGF2 alpha catabolic activity enhanced by endogenous estrogen were greatly decreased by danazol treatment at a dose that did not block the first ovulation in immature rats. When danazol (30 mg) was given s.c. once daily for 2 days to ovariectomized rats, the uterine weight and PGF2 alpha catabolic activity per uterus were clearly increased, and the compensatory increase in FSH levels as a result of castration was not influenced, although the compensatory increase in LH levels was inhibited. These results demonstrate that danazol has a direct action on the ovary and uterus, and give further support to the view put forward in our previous paper that these actions of danazol may contribute to its therapeutic effects.

Administration, Oral↗

Hormone changes in relation to the time of fetal death after prostaglandin-induced abortion.

The changes in unconjugated estradiol-17beta and estriol, progesterone and chorionic somatomammotropin (HCS) in peripheral plasma have been studied in 18 women at 30-minute intervals following intra-uterine prostaglandin E2 administration for therapeutic termination of second trimester pregnancy. The hormonal changes were related to the time of fetal death detected by the disappearance of fetal heart pulsations. Prostaglandin E2 was given by the intra-amniotic route with urea (5 patients) or with intravenous oxytocin (5 patients), or by the extra-amniotic route with intravenous oxytocin (8 patients). Fetal death occurred rapidly with intra-amniotic PGE2, but usually at a late stage with extra-amniotic PGE2. Three fetuses in the extra-amniotic group died at or just before abortion. A variety of fetal heart changes were noted and the time of fetal death did not appear to influence the time of abortion within each treatment subgroup. Estradiol and estriol showed a sligh but persistent fall over 24 hours prior to induction of abortion. A more rapid fall usually occurred after induction, with a consistent fall around the time of fetal death. Progesterone and HCS usually fell much less before and immediately after fetal death. A marked rise in estradiol sometimes occurred before fetal death, particularly in the intraamniotic PGE2 and urea subgroup. Estriol levels declined more rapidly before than after fetal death, whereas fetal death had less consistent effects on the other hormones. All hormones had usually fallen considerably at the time of abortion, and in some individuals marked fluctuations in hormone levels were seen.

Abortion, Induced↗

Effect of cernitin pollen-extract on experimental nonbacterial prostatitis in rats.

BACKGROUND: The treatment for chronic nonbacterial prostatitis (NBP) has not been established. Cernitin pollen-extract (CN-009) is reported to have therapeutic effects for NBP. The effects and mechanisms of CN-009 were investigated. METHODS: Ten-month-old rats were used with administration of estradiol after castration, which were similar to human NBP histologically. Since CN-009 consists of T-60 and GBX, these drugs were administered, respectively. The prostate was evaluated histopathologically including glandular damage (epithelial score), stromal ratio and immunohistochemical assays for epithelial function (PAP), stromal evaluation (Vimentin), cell proliferation (PCNA) and apoptosis (deoxyuridine triphosphate biotin nick end-labeling (TUNEL)). RESULTS: Controls revealed severe acinar gland atrophy and stromal proliferation. CN-009 showed diminished these damages. Epithelial score was better (P < 0.01) and PAP positive materials were more abundant in CN-009 and GBX than in Controls. The stromal ratio was lower in CN-009 (P < 0.01) and T-60 (P < 0.05). There was no difference for PCNA positive cells in the epithelium and stroma, and TUNEL positive cells in epithelium. While, the number of TUNEL positive cells in the stroma of CN-009 and T-60 increased (P < 0.01). CONCLUSIONS: These findings suggest that CN-009 protects acinar epithelial cells mainly by GBX and also inhibits stromal proliferation in association with enhanced apoptosis mainly by T-60.

Acid Phosphatase↗

Some clinical effects of oestrogen-progestogen therapy in surgically castrated women.

This study reports some of the effects of oestrogen and progestogen therapy. forty-nine women who had undergone hysterectomy and bilateral salpingo-oophorectomy took part in a double blind crossover study during which they received ethinyl oestradiol 50 micrograms/day, norgestrel 250 micrograms/day, the combination of these substances "Nordiol" and placebo. Somatic complaints were assessed at monthly interviews and weight and blood pressure recorded. The addition of norgestrel to ethinyl oestradiol therapy resulted in less dryness of skin but significantly increased mastalgia and breast size. There were no significant differences between drugs on amount of facial hair, acne, arthralgia, pruritus vulvae, vaginal discharge, vaginal odour, dyspareunia, weight or blood pressure. There was a significant reduction of diastolic blood pressure with the time duration of the study.

Blood Pressure↗

Clinical, cytological and biological study of the intra-vaginal administration of oestriol (Ortho-Gynest) in post-menopausal patients.

Although some well-defined conditions require a replacement oestrogen therapy, local trophic disorders associated with the decrease of oestriol concentrations after surgical castration or menopause are corrected in a very satisfactory way by local oestrogen therapy. An initial treatment with 0.5 mg oestriol per day for 3 wk followed by a 4-wk maintenance therapy of 2 pessaries per week (2 x 0.5 mg) brings about a clinical cure and normalization of the maturation index in more than 95% of the 48 patients with surgical or natural menopause who received this treatment. The authors insist on the efficacy of this therapeutic approach.

Administration, Topical↗

Host factors and breast cancer growth characteristics.

The rate of growth and spread of breast cancer varies considerably from patient to patient. An observational study was undertaken to identify possible associations between breast cancer growth characteristics and a wide variety of host factors, including demographic, anthropometric, hormonal and dietary variables in 91 patients with breast cancer. Increasing age was associated with favourable growth characteristics, while previous tonsillectomy was associated with adverse growth characteristics. There were no significant associations in anthropometric variables. For postmenopausal women, increasing bioavailability of oestradiol was associated with favourable growth characteristics, while increasing prolactin concentration was associated with adverse growth characteristics. Increasing consumption of sugar, fibre, fruit and vegetables and vitamins was associated with favourable growth characteristics. Consumption of fat (monounsaturated and saturated) was associated with adverse characteristics when adjustment was made for total energy intake. The host environment may play a role in the control of breast cancer growth. In particular, the associations with oestrogen and progesterone receptor status indicate that nutrients may be of value as biological response modifiers in patients having hormonal therapy. This requires further investigation to assess therapeutic potential.

Age Factors↗